Polymorphism is the ability of a compound to crystallize as more than one distinct crystal species. Different polymorphic forms (or polymorphs) have different arrangements or conformations of the molecules in the crystal lattice. If a solid does not possess a distinguishable crystal lattice and the molecular arrangement of molecules is disordered, it is considered amorphous. The amorphous state is structurally similar to the liquid state [W. McCrone, Phys. Chem. Org. Solid State (1965) 2:725767].
Polymorphic forms of a drug substance can have different chemical, physical and physicotechnical properties. Differences can result from e.g. packing of molecules in the crystal structure (density, refractive index, conductivity, hygroscopicity), thermodynamic properties (melting point, heat capacity, vapor pressure, solubility), kinetic properties (dissolution rate, stability), surface properties (surface free energy, interfacial tension, shape, morphology), and mechanical properties (compatibility, tensile strength). These properties can have a direct effect on the ability to process and manufacture the active pharmaceutical ingredient (API) and the drug product. Polymorphism further has pharmacological implications due to altered solid state properties and suitability for a particular formulation. Thus, polymorphism of an API can affect the quality, safety, efficacy and developability of a drug product and is therefore of fundamental importance [D. Giron et al., J. Therm. Anal. Cal. (2004) 77:709].
In addition to polymorphic modifications, an API can be crystallized in different salt forms with an appropriate counterion. Similar to polymorphism, salt forms are varying from each other in the degree of solubility and many other physical and chemical factors, as denoted above. As compared to the free acid or free base of the API, an appropriate salt form might provide improved aqueous solubility, dissolution rate, hygroscopicity, chemical stability, melting point, or mechanical properties.
Solvates, also known as pseudopolymorphs, are crystal forms having either stoichiometric or nonstoichiometric amounts of a solvent incorporated in the crystal lattice. If the incorporated solvent is water, the solvate is commonly known as a hydrate.
Salts and inclusion complexes both are multicomponent systems. Salts are formed by ionic bonding interactions with complete proton transfer between acid and base whereas in inclusion complexes the molecules are neutral in the crystalline state and are connected mainly through hydrogen bonds or Van der Waals interactions [S. L. Morissette et al., Adv. Drug Del. Rev. (2004) 56:275-300].
Cyclodextrins are comprised of six, seven, or eight glucose units, respectively, and have hydrophilic cavity exteriors and hydrophobic cavity interiors [V. J. Stella et al., Adv. Drug Del. Rev. (2007) 59:677-694]. These properties are responsible for their aqueous solubility and ability to incorporate hydrophobic molecular moieties within their cavities. Cyclodextrins can be employed as inclusion complex formers for inclusion complexes with APIs, in which the API is trapped by a cavity of cyclodextrin molecules. It is reported in the literature that the crystal structures of cyclodextrin inclusion complexes are typically dominated by the spatial arrangement of the host molecules. Thereby the cyclodextrin may form a defined packing arrangement similar to a crystalline state, whereas the API does not occupy well defined lattice positions [T. Uyar et al., Cryst. Growth Des. (2006) 6:1113-1119, T. Toropainen et al., Pharm. Res. (2007) 24:1058-1066].
Among the commercially available cyclodextrins, γ-cyclodextrin (γ-CD) is reported to be stable and has been found safe for oral administration [I. C. Munro et al., Regulatory Toxicology and Pharmacology (2004) 39:53-513]. However, γ-cyclodextrins are not used in marketed drug preparations up to now. A monograph has only recently (12/2008) been included in the European pharmacopoeia. The formation of inclusion complexes with cyclodextrins is not predictable and needs comprehensive experimental investigation. In those cases where inclusion complexes with γ-cyclodextrin are formed, most active pharmaceutical ingredients form a 2:1 complex (ratio between inclusion complex former and API). The formation of cyclodextrin inclusion complexes and their guest to host stoichiometries are highly dependent on the molecular structures and the geometrical sizes of the guest molecules [T. Uyar et al., Cryst. Growth Des. (2006) 6:1113-1119].
The compound of formula (I), its manufacture, its pharmacological activity as inverse agonists of the GABA A α5 receptor, and its use for the treatment, prevention and/or delay of progression of various central nervous system (CNS) conditions have been described in WO 2009/071476. Based on its physicochemical properties, the compound of formula (I), as described in WO 2009/071476, is a BCS 2 compound, exhibiting low aqueous solubility and high permeability, according to the biopharmaceutical classification system [G. L. Amidon, H. Lennernas, V. P. Shah, J. R. Crison, Pharm. Res. (1995) 12:413-420]. Hence the limited oral bioavailability is a major issue for oral formulation development.
If anhydrous solid forms of the compound of formula (I), as described in WO 2009/071476, are selected for clinical development, a physical instability in terms of hydrate formation during pharmaceutical processing and/or storage of the drug product is possible. Anhydrous solid form A of the compound of formula (I) as described in WO 2009/071476 and herein, has further been found to be only metastable and hence may convert into different solid forms. Hence there is a need to find new solid forms which feature enhanced physicochemical properties and improved bioavailability.
Further, the discovery of new solid forms of an API (polymorphs, solvates, salts, inclusion complexes) enlarges the repertoire of materials that a formulation scientist has available with which to design a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristics. Therefore, there is a need to find more solid forms of the compound of formula (I).